Direct Crystallization Resolution of Racemates Enhanced by Chiral Nanorods: Experimental, Statistical, and Quantum Mechanics/Molecular Dynamics Simulation Studies

Abstract

Three chiral nanorods of C 14 - l -Thea, C 14 - l -Phe, and C 14 - d -Phe were first synthesized and utilized as heterogeneous nucleants to enhance the resolution of racemic Asp via direct crystallization. Through the statistical analysis from 320 batches of nucleation experiments, we found that the apparent appearance diversity of two enantiomeric crystals of Asp existed in 80 homogeneous experiments without chiral nanorods. However, in 240 heterogeneous experiments with 4.0 wt % chiral nanorods of solute mass added, the appearance of those nuclei with the same chirality as the nanorods was apparently promoted, and that with the opposite chirality was totally inhibited. Under a supersaturation level of 1.08, the maximum ee of the initial nuclei was as high as 23.51%. When the cooling rate was 0.025 K/min, the ee of the product was up to 76.85% with a yield of 14.41%. Furthermore, the simulation results from quantum mechanics (QM) and molecular dynamics (MD) revealed that the higher chiral recognition ability of C 14 - l -Thea compared to C 14 - l -Phe that originated from the interaction difference between C 14 - l -Thea and Asp enantiomers was larger than that between C 14 - l -Phe and Asp enantiomers. Moreover, the constructed nanorods exhibited good stability and recyclability.

Enhanced Direct Crystallization Resolution of Racemates Mediated in Chiral Ionic Liquid Cosolvent Mixtures: Experimental, Statistical, and QM Simulation Studies

“…46 The absolute value ΔBE of Thr enantiomers between [Hmim] 2 [L-MA] is larger than that between [Hmim][L-2-AbA], meaning the 11a), respectively, and the average recovery ratio approaches 96.5% of CILs (Figure 11b), indicating that CILs possess a continuously effective separation ability with a high reusability to promote the yield and yield ratio of products. 71 Besides, the recovered CILs after six recycles are re-characterized by 1 H NMR, FTIR spectra, and viscosity analyses (Figures S10 and S11 and Table S7, Supporting Information), confirming that the nature remains the same as the freshly prepared CILs, revealing that CILs maintain the stability in the reduplicative direct crystallization resolution. Particularly, the recycled direct crystallization resolution process is feasible owing to the stability and recyclability of the CILs.…”

“…With the optimal conditions of the addition rate of 0.05 mL·min –1 and seeds of 20% being fixed, the yield ratios mediated in the recovered CCM-0.3 and recovery ratios of CILs during six recycles are depicted in Figure . For six recycles of [Hmim]­[ l -2-AbA] and [Hmim] 2 [ l -MA] CM-0.3, the yield ratios correspondingly drop from 24.36 to 20.09% along with 27.47 to 23.29% (Figure a), respectively, and the average recovery ratio approaches 96.5% of CILs (Figure b), indicating that CILs possess a continuously effective separation ability with a high reusability to promote the yield and yield ratio of products . Besides, the recovered CILs after six recycles are re-characterized by 1 H NMR, FTIR spectra, and viscosity analyses (Figures S10 and S11 and Table S7, Supporting Information), confirming that the nature remains the same as the freshly prepared CILs, revealing that CILs maintain the stability in the reduplicative direct crystallization resolution.…”

“…Additionally, lower Δ T contributes to the higher absolute ee values of products . It is because the smaller nucleation driving force leads to a longer time for the chiral recognition . Furthermore, the average absolute ee values of nuclei mediated in [Hmim] 2 [MA] CM-0.3 are greater than that in [Hmim]­[2-AbA] CM-0.3, probably because of more selective interactions such as hydrogen bonds along with van der Waals forces between [Hmim] 2 [MA] and chiral solutes …”

“…35 It is because the smaller nucleation driving force leads to a longer time for the chiral recognition. 71 S5. Generally, when methanol as an antisolvent is added, the solubilities of the three Thr species significantly drop.…”

“…In Figure 10a,c 71 Furthermore, the binding energy (BE) can be used to intuitively investigate the mechanism of chiral recognition, as shown in Table 2. Clearly, ΔBE is less than 0, indicating that L-ILs are inclined to perform a chiral recognition with the D enantiomer.…”